Methods for remodeling neuronal and cardiovascular pathways

ABSTRACT

The present invention provides a method of administration of an agent which acts to remodel neuronal or vascular pathways for the long term management of sexual dysfunction in both males and females. In a preferred embodiment, the invention provides a method of ameliorating or reversing pathogenic vascular degradative modeling in the ilio-hypogastric-pudendal arterial bed and genitalia comprising administering to a human patient in need of such treatment a therapeutically effective amount of an anti-pressor agent. The anti-pressor agent comprises one or more compounds selected from the therapeutic classes of direct vasodilators such as hydralazine and NO donors, ACE inhibitors, angiotensin-II receptor antagonists, α 1 -adrenergic receptor antagonists, β-adrenergic receptor antagonists, calcium channel blockers, and phosphodiesterase inhibitors. The anti-pressor agent may be co-administered with a diuretic compound, and is administered either chronically at low dose, or for short periods of time at doses higher than are typically used for the treatment of hypertension. In certain embodiments of the method of the invention, the anti-pressor agent is co-administered with a diuretic agent and/or prostaglandin-E 1 .

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to application Ser. No.09/382,749 filed Aug. 25, 1999 which in turn claims priority toprovisional application Ser. No. 60/098,178 filed Aug. 26, 1998.

TECHNICAL FIELD

[0002] The present invention relates to medical methods of treatment,pharmaceutical compositions, and use of anti-pressor agents tomanufacture such pharmaceutical compositions. More particularly, thepresent invention concerns the administration of an agent which acts toremodel neuronal or vascular pathways for the long term management ofsexual dysfunction in both males and females.

BACKGROUND OF THE INVENTION

[0003] The physiology of an erection or sexual arousal in both the maleand female involves central nervous system initiation, neural pathwayactivation, and vascular smooth muscle relaxation. This signalingmediates vasodilation of the penile, clitoral labial, and vaginalarterial blood vessels and the trabecular meshwork of smooth muscle. Theresulting decrease in vascular resistance promotes an increase inarterial inflow and the filling of the corpora cavernosa in the penisand clitoris. Subsequent to there being an appropriate high rate ofinflow, the cavernosal “filling” results in occlusion of the sub-tunicalveins and full rigidity. The rate of inflow is critical because if thereis not enough volume change, venous occlusion can not take place. Aselective structurally-based increase in penile resistance produces asubstantial impediment to inflow. That is, if penile or clitoralvascular structure, or the vascular structure immediately “up-stream”from the genitalia, is more constrained than the rest of thecirculation, there would be a “mismatching” of perfusion pressure andselective resistance, i.e. genital arterial insufficiency. On the otherhand, it is likely that when hypertension is first established and thereis a generalized up-regulation of structurally-based vascular resistancein all vessels, there would not be any deleterious effect on erectilefunction because of a “matching” between perfusion pressure andresistance. That is, despite the hypertrophy of the penile vasculature,the arterial pressure is proportionally elevated thereby allowing foradequate blood flow to the penis.

[0004] Pathological changes in the genital vasculature and alterationsin function control systems have been shown to have a deleterious impacton erectile dysfunction. Local factors such as endothelin andsympathetic nerve mediated release of catecholamines have been shown tobe important players in detumescence, but they also are likely toincrease trophic responses in this tissue. The physiology of penile andclitoral erection and the structural maintenance of the tissue dependsupon a balance between control systems that involve endothelial cells,vascular smooth muscle cells, fibroblasts, extracellular matrix, andnerves. Any shift in the balance of these control systems to eithertowards trophic responses such as vascular hypertrophy, focal fibrosis,or generalized production of the extracellular matrix or to the extremesof functional control systems can result in erectile dysfunction.Further, as structure and function are so closely related, it isbecoming increasingly important in understanding the mechanisms oferectile dysfunction that we investigate the reciprocal impact ofstructural changes on function and of changes in functional controlsystems on structure.

[0005] The clitoris is the homologue of the penis, arising from theembryological genital tubercle. As a result, the two organs have similarstructural and arousal response mechanisms. The clitoris consists of acylindrical, erectile organ composed of three parts: the outermost glansor head, the middle corpus or body, and the innermost crura. The body ofthe clitoris consists of paired corpora cavernosa of about 2.5 cm inlength and lacks a corpus spongiosum. During sexual arousal, blood flowto the corpora cavernosa of the clitoris cause their enlargement andtumescence.

[0006] The clitoris plays a major role during sexual activity in that itcontributes to local autonomic and somatic changes causing vaginalvasocongestion, engorgement, and subsequent effects, lubricating theintroital canal making the sexual act easier, more comfortable, and morepleasurable.

[0007] Vaginal wall engorgement enables a process of plasma transductionto occur, allowing a flow through the epithelium and onto the vaginalsurface. Plasma transduction results from the rising pressure in thevaginal capillary bed during the sexual arousal state. In addition,there is an increase in vaginal length and lumenal diameter, especiallyin the distal ⅔ of the vaginal canal.

[0008] It has been well established that the generation of a penile andclitoral erections and vaginal and labial engorgement are greatlydependent on adequate blood flow to vascular beds which feed theseorgans. Both smooth muscle relaxation of the corpora cavernosa as wellas the vasodilation of genital arterial vessels mediate thephysiological response. One of the major fundamental etiologies oferectile dysfunction is, thus, inadequate genital arterial inflow. Ifthere is an inappropriate structural narrowing in the supportingvasculature that is not associated with an increase in perfusionpressure, the blood flow into the organs at maximum dilation may bereduced and therefore be insufficient for the generation of an erection.There is increasing recognition that erectile dysfunction, althoughassociated with, may appear prior to the onset of clinical signs ofcardiovascular disease and therefore may be an early harbinger ofprogressing changes.

[0009] In both the male and female human, the aorta bifurcates on thefourth lumbar vertebra into the common iliac arteries. The common iliacarteries pass laterally, behind the common iliac veins, to the pelvicbrim. At the lower border of the fifth lumbar vertebra, the common iliacarteries divide into internal and external branches. The internal iliacartery supplies blood to all of the organs within the pelvis and sendbranches through the greater sciatic notch to supply the gluteal musclesand perineum. After passing over the pelvic brim, the internal iliacartery divides into anterior and posterior trunks.

[0010] The anterior trunk of the internal iliac artery branches into thesuperior vesical artery, the inferior vesical artery, the middle rectalartery, the uterine artery, the obturator artery, the internal pudendalartery, and the inferior gluteal artery. The internal pudendal arterysupplies blood to the perineum. The artery passes out of the pelvisaround the spine of the ischium and back on the inside surface of theischeal tuberosity and inferior ramus to lie in the pudendal canal. Thebranches from the internal pudendal artery are the inferior rectalartery which supplies the anal sphincter, skin and lower rectum; theperineal artery which supplies the scrotum in the male and the labia inthe female; the artery of the bulb which supplies erectile tissue, thedeep dorsal arteries of the penis or deep artery of the clitoris.

[0011] It has been demonstrated in several forms of experimentalhypertension that “slow pressor mechanisms” such as hypertrophicstructural changes in the vasculature can almost completely account forthe long-term resistance changes associated with the elevated arterialpressure. Based on Poiseuille's law, it has been shown that vascularresistance in an intact vascular bed is a function of the overallhemodynamic effect of all lumen radii, the number of blood vessels, thelength of the vessels and the blood viscosity. In hypertension,increased vascular resistance is most potently conferred by astructurally-based decrease in the radius of the lumen of arterioles andsmall arteries and also potentially by arteriolar rarefaction wherebyeven a small change in the average arteriolar radii throughout avascular bed has a dramatic influence on the resistance to flow.Further, it has been demonstrated that such structural changes canprecede the onset of hypertension and therefore may be an initiatingmechanism.

[0012] Vascular beds in which there is chronic diminished blood flowsuffer a degree of pathogenic vascular degradative modeling over time inresponse to static or circulatory hypoxia. That is, as a normal reactionto diminished blood flow, the lumen in these arteries diminishes indiameter over time, causing decreased blood flow and/or higher pressureduring periods of peak blood flow. Those portions of theilio-hypogastric-pudendal arterial bed which directly feed blood to thesex organs are examples of such less frequently used arterial beds.Because incidents of major blood inflow to the sexual organs are lessfrequent than to most other organs, a gradual hypoxic response is seenover time in the vasculature directly feeding these organs and in theorgans themselves. The body has a self-regulating mechanism to combatthis pathogenic modeling: it is known, for example, that in the humanmale there are a number of spontaneous nocturnal erections which occuras a result of the body's mechanism for combating hypoxia in peniletissue. Nevertheless, the arteries in a normal flaccid penis and theun-enlarged clitoris and labia are constricted. As a result, typicaloxygen concentrations in such tissues are closer to venous rather thanarterial oxygen levels. Periodic vasodilation of the penis and clitorisincreases oxygen levels in these tissues. The higher oxygen levelssupplied to tissue in the penis and clitoris, as well as vasodilationitself, shut down adverse metabolic processes such as TGF-b productionand pathogenic vascular wall modeling which result in long term tissuedamage.

[0013] Therefore, it is differential changes in genital vascularresistance that is likely to be a critical issue in erectile function.That is, if such vascular structural changes take place in the genitaliain the absence of hypertension or systemic changes in vessel structurethere would not be the increase in arterial pressure required tocompensate for the increased resistance. It may be that this conditioncould occur as an early indicator of progressing cardiovascular disease.The appearance of erectile dysfunction preceding the global clinicalsigns of hypertension may, in fact, suggest an increased susceptibilityof this vascular bed to pathological changes.

SUMMARY OF THE INVENTION

[0014] In its principal embodiment, the present invention provides amethod for the long term management of sexual dysfunction in males andfemales by administering a therapeutic agent which remodels neuronal orvascular pathways. In a preferred embodiment, the invention provides amethod of ameliorating, inhibiting or reversing pathogenic vasculardegradative modeling in the ilio-hypogastric-pudendal arterial bed andgenitalia comprising administering to a human patient in need of suchtreatment a therapeutically effective amount of an anti-pressor agent.In one embodiment, the present invention provides the use of ananti-pressor agent for the manufacture of pharmaceutical compositionsfor ameliorating, inhibiting or reversing pathogenic vasculardegradative modeling in the ilio-hypogastric-pudendal arterial bed andgenitalia.

[0015] The anti-pressor agent is administered chronically at low dosesranging between about one-twentieth to about one-half the dose requiredto evoke vasodilation in a patient exhibiting normal circulation or,alternatively, is administered over a period of time ranging betweenabout five days to about 21 days at higher doses ranging between about1.5 to about 3 times the dose required to evoke vasodilation in apatient exhibiting normal circulation.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0016] IN THE DRAWING:

[0017]FIG. 1 is a representative cumulative α₁-adrenoreceptorconcentration-response curve for administration of several doses ofmethoxamine (MXA) to a spontaneously hypertensive rat. Arrows indicatethe point of drug delivery to the penile vascular bed at theconcentrations labeled in the Figure. Each concentration of MXA wasinfused for a period of ten minutes, at which time a plateau wasreached. The point marked “yield” in the Figure represents the pressureat maximum constriction of the blood vessels in the vascular bed. Thismaximum constriction was achieved by administration of a “cocktail”containing a mixture of vasopressin (20 μg/mL), angiotensin-II (200μg/mL), and methoxamine (64 μg/mL).

[0018]FIG. 2 shows the average α₁-adrenoreceptor concentration-responsecurves for administration of methoxamine (MXA) to both the penilevascular bed and hindlimb vascular bed perfusion preparations of thespontaneous hypertensive rat (SHR) and the normotensive Sprague-Dawleyrat (SD).

[0019]FIGS. 2a and 2 b represent, respectively, the curves foradministration to the penile vascular beds of the SHR and SD ratstrains.

[0020]FIGS. 2c and 26 represent, respectively, the curves foradministration to the hindlimb vascular beds of the SHR and SD ratstrains.

[0021]FIG. 3a shows the structurally-based vascular resistance assertedat maximum dilation for the penile and hindlimb perfusion vascularpreparations for the spontaneously hypertensive rat (SHR) and thenormotensive Sprague-Dawley rat (SD).

[0022]FIG. 3b shows the corresponding structurally-based vascularresistance asserted at maximum constriction for the penile and hindlimbperfusion vascular preparations for the spontaneously hypertensive rat(SHR) and the normotensive Sprague-Dawley rat (SD).

[0023]FIG. 4 is a schematic representation depicting structuraldifferences in blood vessels in the spontaneously hypertensive rat (SHR)and the normotensive Sprague-Dawley rat (SD) and the expected impact onresistance to blood flow.

DETAILED DESCRIPTION

[0024] The present invention contemplates the use of anti-pressor agentsto remodel vasculature in the arterial beds supplying blood to the sexorgans, and in the vascularity of the sex organs themselves. There hasbeen some controversy in the literature as to the correct definition ofthe term “vascular remodeling,” as evidenced by the exchange of lettersin the Journal of Hypertension, 15: 333-337 (1997). The controversy inthe nomenclature centers, in part, around the use of the terms“hypotrophic,” “eutrophic,” and “hypertrophic” as modifiers for the term“remodeling” as well as the use of the prefix “re-” in the word“remodeling.”

[0025] The “trophic” terms have been objected to because of theirsuggestion that some sort of growth change accompanies the observedvascular changes. The term “remodeling” was initially applied in theliterature to the observation in spontaneously hypertensive rats and inhypertensive humans that the interior lumen radius (r₁) of blood vesselswas greatly diminished while vessel wall mass (w) remained constant. Theresult was an observed increase in the ratio of w/r₁ which correlatedwith blood pressure elevation. The term “remodeling” was applied to theobserved phenomenon, primarily because of the surprising consistency intotal wall mass. It was thought that some sort of remodeling of theinternal cellular structure of the blood vessel had occurred whichpermitted a change in lumen radius without a corresponding change invessel wall mass.

[0026] The “re-” prefix has been objected to mainly because of thesuggestion that some sort of “modeling” of the vasculature has alreadyoccurred, and subsequent changes (for good or ill) result in a“re-”modeling of those changes.

[0027] Lacking a general consensus of the term “vascular remodeling” inthe medical community, the term “pathogenic vascular degradativemodeling” will be applied, throughout this specification and theappended claims, to denote the pathogenic or degradative increase in theratio w/r₁ of vasculature, irrespective of the cause. The term “vascularremodeling” as used throughout this specification and the appendedclaims will mean the amelioration, inhibition or reversal of pathogenicvascular degradative modeling; that is the amelioration, inhibition orreversal of the decrease in the ratio of vascular w/r₁.

[0028] The term “anti-pressor agent” as used herein denotes atherapeutic agent which acts either directly or indirectly to lowerblood pressure. The term anti-pressor agent is chosen, rather than themore specific term “antihypertensive” agent, because the inventioncontemplates the use of agents which are effective to increase vascularflow in both hypertensive and normotensive patients. Anti-pressor agentscontemplated for use in the method of the present invention includeagents which act to bring about a lowering of blood pressure by any of anumber of different physiological mechanisms. Anti-pressor agentsinclude compounds belonging to a number of therapeutic classes basedupon their mechanism of action, even though the therapeutic outcome isthe same. Anti-pressor agents suitable for the method of this inventioninclude compounds which are direct-acting vasodilators such as NO donorsand hydralazine. Other suitable anti-pressor agents are compounds whichact to inhibit the enzyme which converts the less potent decapeptidevasoconstrictor, angiotensin-I, to the more potent octapeptidevasoconstrictor, angiotensin II (so-called angiotensin-II convertingenzyme inhibitors or “ACE inhibitors”), as well as agents which blockthe binding of angiotensin-II to the AT₁ receptor (“angiotensin-Ireceptor antagonists”). Anti-pressor agents useful in the method of thepresent invention also include vasodilating agents which act atα₁-adrenergic receptors or β-adrenergic receptors in the smooth muscleof vascular walls (“α₁-adrenergic receptor antagonists” and“β-adrenergic receptor antagonists”), as well as agents which act todecrease intracellular calcium ion concentration in arterial smoothmuscle (“calcium channel blockers”). Suitable anti-pressor agents foruse in the present invention also include activators of the enzymesguanylyl cyclase and adenyl cyclase such as YC-1 and forskolin,respectively. PGE₁ (prostaglandin-E₁), which acts both as ananti-pressor agent and as a sexual response initiator, is also suitablefor use in the invention. Also contemplated as falling within the scopeof the invention for use as anti-pressor agents are phosphodiesteraseinhibiting agents, particularly type-3 and type-5 phosphodiesteraseinhibitors. Antagonists of PDE-5 (phosphodiesterase type 5), the enzymeprimarily responsible for the degradation of cyclic guanosinemonophosphate (cGMP), produce an increase in levels of cGMP, which, byway of “cross-talk, ” also decreases the activity of PDE-3, the enzymeprimarily responsible for the degradation of cyclic adenosinemonophosphate (cAMP). Thus, increasing levels of cGMP acts to inhibitthe PDE-3 enzyme, thereby blocking the degradation of cAMP and causingan increase in cAMP levels. Thus, inhibition of either PDE-5 or PDE-3results in an overall increase in concentrations of cAMP and cGMP.

[0029] Specific examples of NO donors include glyceryl trinitrate,isosorbide 5-mononitrate, isosorbide dinitrate, pentaerythritoltetranitrate, sodium nitroprusside, 3-morpholinosydnonimine,molsidnomine, S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione,N-hydroxyl-L-arginine, S,S-dinitrosodthiol, and NO gas.

[0030] ACE inhibitors include benzazapine compounds such as benazepril,and libenzapril; 6H-pyridazino[1,2-a]diazepine derivatives such ascilazapril; 2,3-dihydro-1H-indene compounds such as delapril; L-prolinederivatives such as alacepril, captopril, ceronapril, enalapril,fosinopril, lisinopril, moveltipril and spirapril; oxoimidazolinederivatives such as imidapril; 1,4-dihydropyridine compounds such aslacidipine; iso-quinoline carboxylic acid derivatives such as moexipriland quinapril; 1H-indole carboxylic acid derivatives such as pentopriland perindopril; hexahydroindole carboxylic acid derivatives such astrandolapril; cyclopenta[b]pyrrole carboxylic acid derivatives such asramipril; and 1,4-thiazepine compounds such as temocapril.

[0031] Angiotensin-II receptor antagonists useful as anti-pressor agentsin the method of this invention include eprosartan, irbesartan,losartan, and valsartan.

[0032] α₁-Adrenergic receptor antagonists include substituted phenylderivatives such as midrodrine, phenoxybenzamine, tamsulosin;substituted naphthyl derivatives such as naphazoline; aminoquinazolinederivatives such as alfuzosin, bunazosin, doxazosin, prazosin, terazosinand trimazosin; benzamide compounds such as labetolol; carbazolederivatives such as carvedilol; dimethyluracil derivatives such asurapidil; imidazolidinyl derivatives such as apraclonidine, clonidine;dihydroimidazole derivatives such as phentolamine; indole derivativessuch as indoramin; and 1,2,4-triazolo[4,3-α]pyridine compounds such asdapiprazole.

[0033] Calcium channel blockers include benzothiazepine compounds suchas diltiazem; dihydropyridine compounds such as nicardipine, nifedipine,and nimopidine; phenylalkylamine compounds such as verapamil;diarylaminopropylamine ether compounds such as bepridil; andbenimidazole-substituted tetralin compounds such as mibrefadil.

[0034] Phosphodiesterase inhibitors include bipyridone compounds such asamrinone; and dihydropyrazolopyrimidine compounds such as sildenafil.Sildenafil functions as a selective type-5 (i.e. c-GMP specific)phosphodiesterase inhibitor, and acts to decrease the metabolism ofc-GMP, the second messenger in nitric oxide mediated erectile response.An oral formulation of this medication has proven to be safe andeffective in improving erectile duration and rigidity. In females,nitric oxide/NOS exists in human vaginal and clitoral tissue.Sildenafil, alone or in combination with other vasoactive agents, iseffective for the long term management of sexual dysfunction for thetreatment of vasculogenic male or female sexual dysfunction.

[0035] Pharmaceutical Compositions

[0036] Pharmaceutical compositions which are useful in the method of thepresent invention comprise one or more compounds defined aboveformulated together with one or more non-toxic pharmaceuticallyacceptable carriers. The pharmaceutical compositions may be speciallyformulated for oral administration in solid or liquid form, forparenteral injection, or for vaginal or rectal administration. Theformulations may, for example, contain a single therapeutic agentselected from ACE inhibitors, angiotensin-1 (AT₁) receptor antagonists,oc-adrenoreceptor antagonists, β-adrenergic receptor antagonists,direct-acting vasodilators, NO donors, calcium channel blockers,phosphodiesterase inhibitors, or a combination of two or more agentsselected from the same or different therapeutic categories. Moreover, acombination of one or more therapeutic agents from the groups listedabove may be combined with a diuretic agent of the class well known inthe art.

[0037] To enhance delivery to genital vasculature, combined systemicdelivery with topical administration of an erectogenic initiator is alsocontemplated within the scope of this invention. In this manner theanti-pressor drug is delivered to target regions at a markedly enhancedrate. Since prostaglandin-E, acts both as an anti-pressor and as adirect sexual response initiator, one or more therapeutic agents fromthe groups listed above can be administered in combination therapy withprostaglandin PGE₁. The co-administered PGE, may be administered by anyof the routes discussed below, with topical application being apreferred route.

[0038] The pharmaceutical compositions of this invention can beadministered to either systemically or locally to humans and otheranimals. Systemic routes include oral, parenteral, intracisternal,intraperitoneal, trans-cutaneous (by injection or patch), buccal,sub-lingual administration, or by means of an oral or nasal spray. Theterm “parenteral” administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarterial injectionand infusion. Local administration routes include vaginal, rectal,intraurethral, trans-urethral, by intra-cavernosal injection, or topicaladministration.

[0039] Pharmaceutical compositions of this invention for parenteralinjection comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous careers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

[0040] These compositions may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various and bacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

[0041] In some cases, in order to prolong the effect of the drug it isdesirable to slow the release or absorption of the drug followingsubcutaneous or intramuscular rejection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material with lowwater solubility. The rate of absorption of the drug then depends uponits rate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

[0042] Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(othoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

[0043] The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

[0044] Solid dosage forms for oral administration include capsules,tablets, pills, powders, and granules. In such solid dosage forms theactive compound is mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and silicic acid, b) binders such as, forexample, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and 1) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case, of capsules,tablets and pills, the dosage form may also comprise buffering agents.Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

[0045] The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

[0046] Liquid dosage forms for oral administration includepharmaceutically acceptable emulsions, solutions, suspensions, syrupsand elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oils (in particular, cottonseed, ground nutcorn, germ olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

[0047] Suspensions, in addition to the active compounds, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth,and mixtures thereof.

[0048] Compositions for rectal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum and release the active compound,

[0049] Compounds of the present invention can also be administered inthe form of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods for the formation of liposomes are known in the art. See, forexample, Prescott, Ed., Methods in Cell Biology, Volume XIV AcademicPress, New York, N.Y. (1976), p. 33 et seq.

[0050] Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is well known within themedical art to determine the proper dose for a particular patient by the“dose titration” method. In this method, the patient is started with adose of the drug compound at a level lower than that required to achievethe desired therapeutic effect. The dose is then gradually increaseduntil the desired effect is achieved. Starting dosage levels for analready commercially available therapeutic agent of the classesdiscussed above can be derived from the information already available onthe dosages employed for the use of the compound as an antihypertensiveagent. In a chronic, or long-term dosing regimen to remodel thevasculature in the genitalia and in vascular beds feeding the genitalia,lower doses ranging between about {fraction (1/20)} to about ½ the dosesnormally given to combat hypertension are used. In short term, acute, or“burst-mode” therapy, the compounds are administered in doses rangingbetween 1 to 3 times the amounts generally prescribed for hypertension.In these situations, however, appropriate precautions should be taken bythe attending physician to closely monitor untoward side-effectspeculiar to each particular therapeutic agent.

[0051] For the preferred therapeutic agents in the method of the presentinvention, namely ACE inhibitors, generally dosage levels of about 1 mgto about 300 mg, more preferably of about 5 mg to about 150 mg of activecompound per kilogram of body weight per day are administered orally toa patient, with the dose levels appropriately adjusted if the route ofadministration is other than oral. If desired, the effective daily dosemay be divided into multiple doses for purposes of administration, e.g.two to four separate doses per day.

[0052] Biological Data

[0053] A. Demonstration that the Sex Organs are Not Protected fromPathological Vascular Degradative Modeling

[0054] 1 Methodology

[0055] Male spontaneously hypertensive (SH) rats weighing between246-313 g, and normotensive Sprague-Dawley (SD) rats weighing between246-440 g were obtained from Charles River Laboratories (Montreal,Quebec, Canada). The animals were maintained in individual cages with a12 hour light/12 hour dark cycle, and a room temperature of 22-24° C.They were provided with standard rodent chow and tap water ad libitumand were acclimated to the room for at least two days before theexperiments. All procedures were carried out in accordance with theguidelines set out by the Canadian Council on Animal Care.

[0056] 2. Penile Vascular Resistance Properties

[0057] Penile perfusion preparations were made using the procedureestablished by Banting, J. D., et al., “Isolation and Perfusion of thePudendal Vasculature in Male Rats. J Urol., 2: 587-590 (1995). A heatedchamber served to maintain the ambient temperature and the entirepreparation at 37-38° C. The perfusate was held in a reservoir andpassed through a heating and a bubble trapping/mixing chamber connectedto a single peristaltic pump (Minipuls 2 Pump, Gilson, Inc., 3000 W.Beltline Highway, Middleton, Wis. USA 53562). An injection port waslocated distal to the pump for the introduction of pharmacologicalagents to minimize dead volume. Drugs were administered via a HarvardApparatus, Inc. infusion pump (Harvard Apparatus, Inc., 84 October HillRoad, Holliston, Massachusetts 01746). The perfusate was aTyrode-dextran solution consisting of a mixture of 20 mg of KCI, 32.3mgof CaCl.H₂O, 5.1 mg of MgCI₂.6H₂O, 6.2 mg of NaH2PO₄.2H₂O, 155 mg ofNaHCO₃, 100 mg of glucose, and 800 mg of NaCl in each 100 mL of fluid.The solution was maintained at pH 7.4, and a temperature of 37-39° C.,and oxygenated with 95% O₂ and 5% CO₂. The rats were anaesthetized(sodium pentobarbital 60 mg/kg body weight i.p.) and heparinized (1000IU/kg, i.v.). The bilateral isolation of penile vasculature was achievedby ligating all of the branching arteries except for the pudendal; thenthe abdominal aorta was cannulated proximal to the iliac bifurcationwith a single lumen catheter. The catheter was connected to theperfusion apparatus via a pressure transducer for arterial pressurerecording. After sectioning the vena cava and spinal cord to removevenous resistance and to eliminate neural influences, a flow ofperfusate (1 mL/min per kg body weight) through the abdominal cannulawas initiated. The perfusion pressure was continuously recorded on adata acquisition system (MacLab, AD Instruments, Houston, Tex.). Theperfusate was infused for twenty minutes to flush the penile vasculatureof blood and obtain a stable pressure before the beginning of anyexperiment. Following this, sodium nitroprusside (20 μg/mL) was infusedto induce maximum vasodilation. The flow rate-perfusion/pressurerelationship was determined by measuring the pressure at minimumvascular resistance at flow rates of 0.5, 1.0, 2.0, 4.0 mL/min per kg ofbody weight. A cumulative α₁-adrenoreceptor concentration-response curveto methoxamine (2.5, 5, 10, 25, 50 μg/mL was then generated. Eachconcentration of methoxamine was infused for a duration of 10 minutes,at which time a plateau was reached. Subsequently, a continuousinjection of a cocktail containing a supramaximal concentration ofvasoconstrictors (vasopressin, 20.5 μg/mL, angiotensin-II, 200 ng/mL;methoxamine, 64 μg/mL; Sigma, St. Louis, Mo., 63178) was given to ensurethat maximum constrictor response that was not dependent upon theactivation of a single receptor type was achieved. A second injection ofthe constrictor cocktail was administered to ensure the tissue “yield”was maximum constriction. This “yield” induced by themulti-vasoconstrictor cocktail has been demonstrated to correlatedirectly with the bulk of medial vascular smooth muscle cells in theresistance vasculature. A typical perfusion pressure tracing from thisprotocol can be seen in FIG. 1. At the end of the concentration-responserelationship, the aorta was cut distal to the catheter, and a baselineflow-pressure curve was recorded again. This was done to ensure thatpressure fell to zero and to account for any false pressure readingsthat may have resulted due to movement of the catheter during theexperiment.

[0058] 3. Hindlimb Vascular Resistance Properties

[0059] The hindlimb perfusion preparation was adopted from a techniqueoriginally designed by Folkow et al., Acta Physiol Scand., 80: 93-106(1973), as modified by Adams et a., Hypertension, 14: 191-202 (1989).The perfusion experiment was performed as described above. Drugs wereadministered into the mixing chamber via a Harvard Apparatus infusionpump. The rats were anaesthetized (Inactin, 100 mg/kg of body weight,i.p.) and heparinized (1000 IU/kg of body weight, i.v.). Following amidline abdominal incision, the abdominal aorta was cannulated proximalto the iliac bifurcation with a double lumen catheter (Storz, St Louis,Mo., USA), and the catheter was extended down the right common iliacartery. One lumen of the catheter was connected to the perfusionapparatus, while the other was connected to a pressure transducer forarterial pressure recording. The rat was perfused at a constant flowrate (2 mL/min per 100 g of body weight) and the experiments werecarried out as described above. The flow rate/perfusion pressurerelationship was recorded at flow rates of 0.5, 1.0, 2.0, 4.0 mL/min per100 g of body weight. A cumulative α₁-adrenoreceptorconcentration-response curve to methoxamine (0.5, 1, 2, 4, 8, 16, 32, 64μg/mL) was then generated. Each concentration of methoxamine was infusedfor a duration of 5 minutes, at which time a plateau was reached.Subsequently, a bolus injection of a cocktail containing a supramaximalconcentration of vasoconstrictors was given as above. At the end of theconcentration-response relationship, the iliac artery was cut distal tothe catheter, and the flow pressure curve was monitored again.

[0060] Flow rates for the hindlimb perfusion experiments were determinedbased on expected flow rates of exercising skeletal muscle at maximumdilation. The flow rate used resulted in a perfusion pressure at maximumdilation between 20-25 mm Hg which is well within the expected range.After checking several flow rates in the penile perfusion, a rate wasobtained that resulted in a similar perfusion pressure at maximumdilation. The flow rates chosen also allow for the assessment at maximumconstriction. This allowed for comparison between strains.

[0061] 4. Analysis of Data

[0062] All values in the figures and tables were expressed as mean±standard deviation. Results comparing penile and hindlimb vasculaturewere analyzed using the Student's t-test. Differences were considered assignificant at p<0.05.

[0063] 5. Results

[0064] There was no significant difference in the body weight of thespontaneously hypertensive rats in the penile assessment group (267±29g, n=5) and in the hindlimb assessment group (270±5.7 g, n=3). Theaverage body weight of the normotensive Sprague-Dawley rats in thehindlimb assessment group (375±41 g, n=8) was significantly higher thanthat of the of the normotensive Sprague-Dawley rats in the penileassessment group (284±32 g, n=5). However, this was not consideredrelevant because in normotensive adult rats there has been shown to bevery little correlation between body weight and blood pressure (Adams,M. A., et al., Hypertension, 14: 191-202 (1989).

[0065] This hemodynamic analysis had similar effects in most parametersbetween the penile and hindlimb vascular beds within each rat strain.The flow-pressure curve assessed at maximal dilation was similar in boththe penile and the hindlimb vasculatures of spontaneously hypertensiveand normotensive rats as shown in Table 1. These curves were monitoredto ensure a linear increase in perfusion pressure with an increase inflow rate. The increase in the flow rate exerted a radial pressureagainst the vessel wall and resulted in increased pressure. Thespontaneously hypertensive rats trended towards a higher baselinepressure than the normotensive rats. This was observed in both penileand hindlimb vascular beds. These data suggest that spontaneouslyhypertensive rats may have a smaller lumen thus causing them to operateat a higher pressure than normotensive Sprague-Dawley rats even whenthere is no constrictor tone on the vessel. TABLE 1 Maximum ConstrictionWith Methox- Slope amine Slope Group Flow Pressure (mm Hg) Log EC₅₀Methoxamine SHR, 7.15 ± 2.0 172 ± 32 0.95 ± 0.19  1.64 ± 0.21 penile bedSHR,  6.68 ± 0.38  253 ± 25* 0.79 ± 0.15  5.19 ± 3.0* hindlimb bed SD,7.34 ± 2.3 171 ± 36 0.63 ± 0.24  2.03 ± 0.68 penile bed SD, 6.99 ± 3.4191 ± 55 0.78 ± 0.12  3.0 ± 0.99 hindlimb bed

[0066] Table I shows there was a statistically significant difference inmaximum constriction with a supramaximal dose of methoxamine (50 μg/mLfor penile and 64 μg/mL for hindlimb vasculature) between spontaneouslyhypertensive rat hindlimb vasculature (253±25 mmHg) and spontaneouslyhypertensive rat penile vasculature (172±32 mmHg). This difference wasnot observed in normotensive Sprague-Dawley rats. The discrepancy isnovel and requires further assessment. It is expected that higherresponses would be seen in the spontaneously hypertensive rats in botharterial beds, however only the hindlimb vasculature showed asignificant difference between spontaneously hypertensive andnormotensive rats. Average concentration response curves for methoxamineof the two strains in both beds are shown in FIGS. 2a-2 d.

[0067] The EC₅₀ of the concentration response curve shown in Table 1gives the concentration of drug at which there is a 50% response toα₁-adrenoreceptor stimulation. This value would be an indication of thesensitivity of the tissue to this receptor activation. The logs EC₅₀ ofthe methoxamine concentration-response curves were not different forpenile and hindlinb vasculature in both the spontaneously hypertensiveand normotensive rats thus indicating similar sensitivity to thisreceptor stimulation.

[0068] The steepest slope of this curve is given in Table 1. Innormotensive rats, there was no statistically significant difference inslope between penile vasculature (2.03±0.68) and hindlimb vasculature(3.0±0.99). The parameters showed a statistically significant differencebetween spontaneously hypertensive rat penile (1.64±0.21) andspontaneously hypertensive rat hindlimb (5.19±3.0). This was expectedsince the maximal constriction with methoxamine was lower in penilevasculature while the EC₅₀, remained the same.

[0069]FIG. 3 depicts the structurally-based vascular resistanceproperties assessed at both maximum dilation and maximum constriction.There was no significant difference in perfision pressures at maximumdilation within the rat strains. Between the two strains of rats, thepenile vasculature trended towards higher pressures in the hypertensiverat as compared to the normotensive Sprague-Dawley rats, however it didnot reach a level of significance as in the hindlimb. Spontaneouslyhypertensive rats reached a point of maximal constriction with acocktail at a perfusion pressure that was 20% higher than normotensiverats in each vascular bed. There was no statistically significantdifference between the two beds within strain, suggesting that thepenile and hindlimb vasculature undergo similar structural changes ingenetically hypertensive rats. This point demonstrates the increasedmedial thickening that occurs in the hypertensive rats that allows forthe maintenance of higher arterial operating pressures.

[0070] 6. Discussion

[0071] The major findings of the data presented above demonstrate thatthe penile vasculature is not protected from the structural changes thattake place in the other vascular beds of spontaneously hypertensive ratsrelative to normotensive strains. Increased medial thickening andnarrowing of the vascular lumen have been found in blood vessels of awide range of vascular beds of spontaneously hypertensive rats.Therefore, the overall results of the present series of experiments haveshown that the genetic disposition appears to dominate the structureregardless of the vascular bed.

[0072] In the present study a hemodynamic methodology was used tocompare and contrast structurally-based vascular resistance in twovascular beds. The hindlimb bed was chosen for comparison since thevascular resistance properties are well established and anatomically thefeeder vessels of the two beds are common.

[0073] These results demonstrate that the resistance properties atmaximum dilation were similar in the two beds within strains. A generalfinding of studies comparing vascular resistance at minimum tone is thata higher perfusion pressure is normally obtained in SHR compared tonormotensive rats. Thus, findings of elevated resistance properties atmaximum dilation are consistent with there being an overall narrowing ofthe vascular lumen. Resistance properties were further assessed bydetermining the slope of the flow-pressure curve at maximum dilation.This relationship was used to determine whether there were anydifferences in the passive vascular wall elements such as theextracellular matrix components, i.e. if distensibility was alteredthere would be a differential effect on the flow-pressure curves.Further, a thicker medial wall could also result in a stiffer vesselwhich would exhibit less compliance with increasing flow. The lack ofdifference in all of these values suggests that there has been nodifferential change in the components of the vessel wall within thepenile vasculature.

[0074] Assessment of the active components of the vessel walls wasdetermined by inducing a state of maximal vasoconstrictor tone using acocktail of vasoconstrictor agonists. The supramaximal, multiple agoniststimulus produces a maximum constrictor response which is independent ofindividual receptor population changes thereby reflecting only theoverall contractile bulk of the medial smooth muscle cells.

[0075] The findings that sensitivity (EC₅₀) and reactivity (slope) toα₁-adrenoreceptor stimulation were not different between vascular bedsor strains likely indicates that there is a similar stimulus-responsecoupling of the noradrenergic innervation in all of these vessels; i.e.there is a consensus of normal vascular biology. In the schematicdiagram of FIG. 4, the concept of structural changes dominating functionis depicted. Thus, the curves show that, at any given level ofvasoconstrictor tone, the hypertensive circulation will always haveincreased vascular resistance compared to normotensive circulation.Another way of looking at this concept would be that at the same levelof constrictor tone, the normotensive circulation would be able toachieve the same inflow at a proportionately lower perfusion pressurethan the hypertensive circulation.

[0076] Taken together, the findings indicate that the penile vasculaturehas an increased average medial mass coupled with decreased averagelumen. The generation of an erection is based on the flow when vesselsare in a dilated state. Although there was a significant difference inthe perfusion pressure at maximum dilation in the hindlimb vasculatureof spontaneously hypertensive rats (SHR) when compared to thenormotensive Sprague-Dawley (SD) rats, this was not detected in thepenile vascular bed. There was however a trend toward significance whichmay be seen in future studies when animals are used that are geneticallycloser to the spontaneously hypertensive rat, such as the Wistar-Kyotorat (Taconic, 273 Hover Avenue, Germantown, N.Y. 12526) which is a moreappropriate normotensive control. The penile vasculature is more complexthan that of the hindlimb and therefore it may be that differences atmaximum dilation are more difficult to detect. It is also unknownwhether the size of the penis differs between the strains examined inthis study. The length of the vessels changes baseline resistance morethan the maximum constriction response because the maximum dilation isflow-dependent, as there is no constrictor tone on the vessel. Incontrast, maximum constriction responses are based on the bulk musculartissue. Therefore although the point of maximum dilation is expected tobe higher in the penile vasculature of SHR as compared to a normotensivecontrol it may not be detectable using the Sprague-Dawley rats as acomparison based on the suspected differences between the strains.

[0077] B. Therapeutically-induced Vascular Remodeling in PenileVasculature

[0078] 1. Methodology

[0079] Adult spontaneously hypertensive rats (SHR) were treated for 1 ortwo weeks with either enalapril (30 mg/kg of body weight per day) orhydralazine (45 mg/kg of body weight per day). Following this treatment,structurally-based resistance to blood flow in the perfused penilevascular bed and hindlimb vascular bed models were measured using themethods detailed above. Cumulative α₁-adrenoreceptorconcentration-response curves in response to methoxamine were measuredas described above, and the “yield” point determined, following theachievement of maximal vasoconstriction using the vasopressin,angiotensin-II, methoxamine cocktail described above. The animal heartswere excised and weighed. The data are presented in Table 2 below. TABLE2 Left Maximum Ventricle Constriction Weight (g)/ Slope With CocktailBody Flow “Yield” Weight Group Pressure mm Hg) Log EC₅₀ (kg) RatioSHR-E₂ ¹ 6.45 ± 1.31 335 ± 23 8.73 ± 0.26 2.13 ± 0.08 (n = 7) SHR-E₁ ¹6.10 ± 1.5  358 ± 20 7.33 ± 1.39 2.17 ± 0.05 (n = 5) SHR-H² 6.63 ± 0.86353 ± 11 13.56 ± 5    2.37 ± 0.12 (n = 7) Control 7.13 ± 0.63 381 ± 2111.95 ± 5.51  2.46 ± 0.08 (n = 9)

[0080] The data appearing in Table 2 show that enalapril treatmentprogressively regressed (remodeled) cardiac and pudendal vascularstructure over the 2-week period of treatment. The “yield” valuedecreased on average by 12.1%±6.0%, while left ventricular massdecreased by 13.6%±3.2%. Hydralazine treatment was somewhat lesseffective, decreasing the “yield” point by 7.3%±2.9%, and had nosignificant effect on left ventricular weight (decreased of 3.7%±5.0%).

[0081] While there have been shown and described what are believed atpresent to be the preferred embodiments of the present invention, itwill be obvious to those of ordinary skill in the art that variousmodifications can be made in the preferred embodiments without departingfrom the scope of the invention as it is defined by the appended claims.

We claim:
 1. A method of ameliorating, inhibiting or reversingpathogenic vascular degradative modeling in theilio-hypogastric-pudendal arterial bed and genitalia comprisingadministering to a human patient in need of such treatment atherapeutically effective amount of an anti-pressor agent.
 2. The methodaccording to claim 1 wherein said anti-pressor agent comprises one ormore compounds selected independently from the group consisting ofprostaglandin-E₁, ACE inhibitors, AT₁-receptor antagonists,α₁-adrenergic receptor antagonists, β-adrenergic receptor antagonists,calcium channel blockers, direct acting vasodilators, NO donors,activators of guanylyl cyclase, activators of adenyl cyclase, andphosphodiesterase inhibitors.
 3. The method of claim 2 wherein saidanti-pressor agent is an activator of guanylyl cyclase or adenyl cyclaseselected from the group consisting of YC-1 and forskolin.
 4. The methodof claim 2 wherein said anti-pressor agent is a direct actingvasodilator selected from the group consisting of hydralazine and NOdonors.
 5. The method of claim 4 wherein said NO donor is selected fromthe group consisting of glyceryl trinitrate, isosorbide 5-mononitrate,isosorbide dinitrate, pentaerythritol tetranitrate, sodiumnitroprusside, 3-morpholinosydnonimine, molsidnomine,S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione,N-hydroxyl-L-arginine, S,S-dinitrosodthiol, and NO gas.
 6. The methodaccording to claim 2 wherein said anti-pressor agent is anangiotensin-II receptor antagonists selected from the group consistingof eprosartan, irbesartan, losartan, and valsartan, and mixturesthereof.
 7. The method according to claim 2 wherein said anti-pressoragent is an ACE inhibitor selected from the group consisting ofalacepril, benazepril, captopril, ceronapril, cilazapril, delapril,enalapril, fosinopril, imidapril, lacidipine, libenzapril, lisinopril,moexipril, moveltipril, pentopril, perindopril, quinapril, ramipril,spirapril, temocapril, and trandolapril, and mixtures thereof.
 8. Themethod according to claim 2 wherein said anti-pressor agent is anα₁-adrenergic antagonist selected from the group consisting ofalfuzosin, apraclonidine, bunazosin, carvedilol, clonidine, dapiprazole,doxazosin, indoramin, labetolol, midrodrine, naphazoline,phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin,trimazosin, and urapidil, and mixtures thereof.
 9. The method accordingto claim 2 wherein said anti-pressor agent is a calcium channel blockerselected from the group consisting of bepridil, diltiazem, mibrefadil,nicardipine, nifedipine, nimopidine, and verapamil, and mixturesthereof.
 10. The method according to claim 2 wherein said anti-pressoragent is a phosphodiesterase inhibitor selected from the groupconsisting of amrinone and sildenafil.
 11. The method according to claim2 wherein said anti-pressor agent is co-administered with a diureticcompound.
 12. The method according to claim 2 wherein said anti-pressoragent is co-administered with prostaglandin-E₁.
 13. The method of claim1 wherein said anti-pressor agent is administered to a normotensivepatient.
 14. The method of claim 1 wherein said anti-pressor agent isadministered on a chronic basis at a dose ranging between one-twentiethto one-half the dose normally given to a hypertensive patient.
 15. Themethod of claim 1 wherein said anti-pressor agent is administered for aperiod ranging between about three days to about twenty-one days at adose ranging between one to three times the dose normally given to ahypertensive patient.
 16. The method according to claim 14 wherein saidanti-pressor agent is administered to a normotensive patient.
 17. Themethod according to claim 15 wherein said anti-pressor agent isadministered to a normotensive patient.
 18. A method of remodeling thevascular bed which supplies blood to the genitalia, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of an anti-pressor agent.
 19. The method according to claim 18wherein said anti-pressor agent compris es one or more compoundsselected independently from the group consisting of prostaglandin-E₁,ACE inhibitors, AT₁-receptor antagonists, α₁-adrenergic receptorantagonists, β-adrenergic receptor antagonists, calcium channelblockers, direct acting vasodilators, NO donors, activators of guanylylcyclase, activators of adenyl cyclase, and phosphodiesterase inhibitors.20. The method of claim 19 wherein said anti-pressor agent is anactivator of guanylyl cyclase or adenyl cyclase selected from the groupconsisting of YC-1 and forskolin.
 21. The method of claim 19 whereinsaid anti-pressor agent is a direct acting vasodilator selected from thegroup consisting of hydralazine and NO donors.
 22. The method of claim21 wherein said NO donor is selected from the group consisting ofglyceryl trinitrate, isosorbide 5-mononitrate, isosorbide dinitrate,pentaerythritol tetranitrate, sodium nitroprusside,3-morpholinosydnonimine, molsidnomine, S-nitroso-N-acetylpenicillamine,S-nitrosoglutathione, N-hydroxyl-L-arginine, S,S-dinitrosodthiol, and NOgas.
 23. The method according to claim 19 wherein said anti-pressoragent is an angiotensin-II receptor antagonists selected from the groupconsisting of eprosartan, irbesartan, losartan, and valsartan, andmixtures thereof.
 24. The method according to claim 19 wherein saidanti-pressor agent is and ACE inhibitor selected from the groupconsisting of alacepril, benazepril, captopril, ceronapril, cilazapril,delapril, enalapril, fosinopril, imidapril, lacidipine, libenzapril,lisinopril, moexipril, moveltipril, pentopril, perindopril, quinapril,ramipril, spirapril, temocapril, and trandolapril, and mixtures thereof.25. The method according to claim 19 wherein said anti-pressor agent isan α₁-adrenergic antagonist selected from the group consisting ofalfuzosin, apraclonidine, bunazosin, carvedilol, clonidine, dapiprazole,doxazosin, indoramin, labetolol, midrodrine, naphazoline,phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin,trimazosin, and urapidil, and mixtures thereof.
 26. The method accordingto claim 19 wherein said anti-pressor agent is a calcium channel blockerselected from the group consisting of bepridil, diltiazem, mibrefadil,nicardipine, nifedipine, nimopidine, and verapamil, and mixturesthereof.
 27. The method according to claim 19 wherein said anti-pressoragent is a phosphodiesterase inhibitor selected from the groupconsisting of amrinone and sildenafil.
 28. The method according to claim19 wherein said anti-pressor compound is co-administered with a diureticagent.
 29. The method according to claim 19 wherein said anti-pressorcompound is co-administered with prostaglandin-E₁.
 30. The method ofclaim 18 wherein said anti-pressor agent is administered on a chronicbasis at a dose ranging between one-twentieth to one-half the dosenormally given to a hypertensive patient.
 31. The method of claim 18wherein said anti-pressor agent is administered for a period rangingbetween about three days to about twenty-one days at a dose rangingbetween one to three times the dose normally given to a hypertensivepatient.
 32. The method according to claim 30 wherein said anti-pressoragent is administered to a normotensive patient.
 33. The methodaccording to claim 31 wherein said anti-pressor agent is administered toa nornotensive patient.